mmg_233_2013_genetics_genomicswikiaorg-20200214-history
Genome-Wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population
Parkinson's disease (PD), the second most common neurodegenerative disorder and the most common movement disorder, is a disease of the central nervous system characterized by the death of dopaminergic (dopamine producing and utilizing) neurons in a region of the midbrain known as the substantia nigra (Figure 1). The reason for the death of these dopaminergic neurons remains largely unknown, thus Parkinson's is referred to as an idiopathic disease. Interestingly, there is some evidence that there is an increased risk of developing PD in people with exposure to certain pesticides. It is also known that there is a genetic component to PD, and some candidate genes have been identified. Aberrant and insufficient dopamine production and activity within the midbrain, as well as the accumulation of a protein known as alpha-synuclein into structures called inclusion bodies, specifically termed Lewy bodies in PD, constitute the pathological hallmarks of this disease http://en.wikipedia.org/wiki/Parkinson’s. Current estimates put the number of people suffering from PD worldwide somewhere between four and six million. One million people in the United States alone suffer from PD, with an estimated 50,000 - 60,000 new cases diagnosed each year. The CDC rates complications from PD as the 14th leading cause of death in the United States. Although PD may arise in younger persons, it more commonly occurs in people over the age of 50. The primary symptoms of PD include progressive loss of muscle control leading to tremors and trembling of the head and limbs while at rest, rigidity, bradykinesia, and impaired balance followed later by the development of a shuffling gait and difficulty in the ability to walk, talk, and complete simple motor tasks. Some of the secondary symptoms of PD are depression, anxiety and dimensia. Though there is currently no cure for PD, most affected individuals can lead relatively long and productive lives with proper treatment which typically involves a steady, even supply of medication which the body can convert into dopamine 1, http://www.parkinson.org/Parkinson-s-Disease . GWAS Study to Identify Candidate Genes for PD Prior to the 2011 publication of this genome-wide association study (GWAS) study by Liu et al., there had been a total of nine Parkinson's Disease GWAS studies conducted in North American, Europen and Asian populations. Most of these nince GWAS studies confirmed the association of the genetic risk factors SNCA ''and ''MAPT, ''which had previously been identified. Furthermore, two of these studies were able to identify three new genes/loci involved in PD susceptibility: ''PARK16 , BST1 and HLA-DRB5 . Additionally, a meta-analysis had been conducted using the data sets from five of these previous PD GWAS studies that identified SYT11 , ACMSD , STK39 , MCCC1/''LAMP3'' , GAK and CCDC62 /HIP1R ''as potential PD susceptibility genes. Most importantly, the authors of this paper note that all of the PD susceptibility genes and gene associations identified in these previous studies only constitute a small fraction of the predicted heritability of PD, and thus there are many aspects of the genes and gene associations involved in PD that remain to be elucidated http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166909/. The authors chose a small Ashkenazi Jewish population from New York because this group constitutes a cohort that shares a common genetic background and has experienced a major population bottleneck in their not too distant history. The authors felt this relatively genetically homogenous population would be an ideal group of people to in which to analyze single nucleotide polymorphisms (SNPs) with allele frequencies greater than 2% in order to identify both common and rare genetic variants attributed to PD susceptibility. The authors also conducted a replication study using two PD GWAS datasets that were publicly available from the NCBIdatabase of Genotypes and Phenotypes (dbGaP): CIDR/Pankratz et al. 2009 Genome wide association study in familial PD, and NINDS: The National Institute of Neurological Disorders and Stroke http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2627511/, http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(06)70578-6/fulltext. They basically had three main reasons for conducting a replication study: 1) to see how thier Ashkenazi Jewish cohort compared to these datasets, 2) to distinguish between rare genetic variants from the Ashkenazi Jewish cohort that do not appear in these more common data sets versus those that do appear in the more common data sets, and 3) being able to reproduce these previous findings would add more strength to their findings. The three main aims of this study were to use the Ashkenazi Jewish cohort as a case-control discovery data set on which to perform a GWAS using an overall MAF threshold of >2% in order to identify novel PD susceptibility related SNPs, to apply this >2% MAF threshold to the re-analysis of the CIDR/Pankratz ''et al. 2009 and NINDS data sets in order to identify rare genetic variants in these data sets and try to reproduce these findings in their Ashkenazi Jewish cohort, and lastly to take a closer look at the PD susceptibility genes identified in previous GWAS studies and examine how they relate to the findings the three data sets in this study. The combined analysis of the two public data sets and the Ashkenazi Jewish cohort yielded a sample size consisting of 2,050 cases and 1,836 controls 3. Results The authors identified 57 SNPs that exhibited the highest degree of association in the Ashkenazi Jewish cohort (p < 9.9 ×10-5). Of these SNPs, six that were found to be located within gene regions were also found in at least one of the other two independent dbGaP data sets: LOC100505836 (Chr3p24), LOC153328/SLC25A48(Chr5q31.1), UNC13B (9p13.3), SLCO3A1 (15q26.1), WNT3 (17q21.3) and NSF (17q21.3). The authors were also able to successfully replicate the gene region associations that had previously been published for SNCA (Chr4q21; rs3775442, p = 0.037), PARK16 (Chr1q32.1; rs823114 (NUCKS1), p = 6.12 × 10-4), BST1 (Chr4p15; rs12502586, p = 0.027), STK39 (Chr2q24.3; rs3754775, p = 0.005), and LAMP3 (Chr3; rs12493050, p = 0.005) as well as LRRK2 (Chr12q12; rs34637584, p = 1.56 × 10-4) and GBA (Chr1q21; rs2990245 , p = 0.015), the two most commonly found PD susceptibility genes in the Ashkenazi Jewish population. Table 2 PD GWAS.jpg|Top Candidate SNPs from the Ashkenazi Jewish, NINDS and CIDR/Pankratz et al 2009 Datasets. PD GWAS MP.jpg|Manhattan plot for results of GWAS. a) Ashkenazi Jewish, b) NINDS and c) CIDR/Pankratz et al 2009. PD GWAS Fig3.jpg|Regional Association Plots for SNPs significant in the association analysis in the Ashkenazi Jewish dataset a) NSF and WNT3, b) LOC153228/SLC25A48, c) UNC13B, d) SLCO3A1. It is important to note that although these six new PD susceptibility candidate gene regions that were identified did not meet the exactingrequirements of the Bonferroni corrected genome wide significance p-value (p = 9.5 × 10-8), they nevertheless exhibited the strongest potential of containing PD susceptibility genes. These findings are further evidenced by the additional screens that were performed on the 57 candidate SNPs in which the authors checked to see whether or not these SNPs were indeed located in within genes, and that they were observed in at least one of the other independent data sets. They determined that 27 of the 57 identified SNPs were found near to genes and the remaining 30 were found in intergenic regions 3. Conclusions The authors of this study were able to successfully identify six new candidate gene regions involved in PD susceptibility: LOC100505836, SLC25A48, UNC13B, SLCO3A1, WNT3, and NSF by utilizing, as a discovery dataset, an Ashkenazi Jewish cohort case control population together with two additional publicly available data sets used for replication purposes. By utilizing this Ashkenazi Jewish population the authors were successfully able to search for and identify rare genetic variants,defined asa MAF threshold greater than or equal to 2%. Furthermore, the authors were successfully able to examine the degree of association observed in previously reported PD susceptibility genes, and they determined they were indeed comparable to previous reports based on studies in North American and European populations 3. Interestingly, many of the new candidate PD susceptibility genes identified in this study have been shown to have functions related to PD that provide additional confidence that these are indeed bonafide PD susceptibly genes. For example, it has been shown that SLC25A48, UNC13B, and NSF function in both neuronal dopamine and signaling pathways. Ultimately, this study has provided solid evidence on which to build future investigations that will help to further our understanding of PD and its causes 3. References 1. Wikipedia article on Parkinson’s disease. Accessed December 1, 2013. 2. The National Parkinson Foundation website. Accessed December 2, 2013. 3. Liu X, et al. (2011). Genome-Wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population. BMC Medical Genetics ''12:104. 4. Pankratz N, ''et al. (2009). Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum. Genet. 124(6):593-605. 5. Fung HC, et al. (2006). Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet. Neurol. 5(11):911-916.